Outcome predictors in rheumatoid arthritis

Predicting which patients will develop severe rheumatoid arthritis is essential for selection of the most appropriate treatment regimen in early arthritis. The key outcomes in rheumatoid arthritis are persistence of the disease, joint damage (evaluated by X-ray progression), functional dysability, and mortality rate. Rheumatoid factor positivity and number of swollen joints appear to be related to all of these outcomes, while radiologic scores are mostly related to joint damage and health assessment questionnaire (HAQ) to functional dysability. Other relevant prognostic parameters are erythrocyte sedimentation rate or serum C-reactive protein levels, and antibodies to citrullinated peptides

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

A large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide-bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase-thioredoxin (TrxR-Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR-Trx also prevent botulism. On this basis, we propose that ebselen and PX-12, two TrxR-Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism

Histopathology of the synovial tissue : perspectives for biomarker development in chronic inflammatory arthritides

The histopathological and molecular analysis of the synovial tissue has contributed to fundamental advances in our comprehension of arthritis pathogenesis and of the mechanisms of action of currently available treatments. On the other hand, its exploitation in clinical practice for diagnostic or prognostic purposes as well as for the prediction of treatment response to specific disease-modifying anti-rheumatic drugs is still limited. In this review, we present an overview of recent advances in the field of synovial tissue research with specific reference to the methods for synovial tissue collection, approaches to synovial tissue analysis and current perspectives for the exploitation of synovial tissue-derived biomarkers in chronic inflammatory arthritides

B cell autoimmunity and bone damage in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic immune-inflammatory disease associated with significant bone damage. Pathological bone remodeling in RA is primarily driven by persistent inflammation. Indeed, pro-inflammatory cytokines stimulate the differentiation of bone-resorbing osteoclasts and, in parallel, suppress osteoblast function, resulting in net loss of bone. Abating disease activity thus remains the major goal of any treatment strategy in patients with RA. Autoantibody-positive patients, however, often show a rapidly progressive destructive course of the disease, disproportionate to the level of inflammation. The epidemiological association between RA-specific autoantibodies, in particular anti-citrullinated protein autoantibodies, and poor structural outcomes has recently found mechanistic explanation in the multiple roles that B cells play in bone remodeling. In this review, we will summarize the substantial progress that has been made in deciphering how B cells and autoantibodies negatively impact on bone in the course of RA, through both inflammation-dependent and independent mechanisms

Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin

Botulinum neurotoxin serotype F contains the zinc binding motif of zinc endopeptidases. Atomic adsorption analysis of highly purified toxin preparation revealed the presence of one atom of zinc per molecule of toxin, which could be removed with EDTA or o-phenanthroline. The light chain of the neurotoxin was shown to have a zinc-dependent protease activity specific for VAMP/synaptobrevin, an integral membrane protein of synaptic vesicles. Both isoforms of rat VAMP were cleaved at the same site corresponding to the single Gln-Lys peptide bond present in their sequences. This proteolytic activity was inhibited by EDTA, o-phenanthroline, and captopril as well as by VAMP peptides spanning the cleavage site

POS0250 SIGNIFICANT DAMAGE OCCURS EARLY IN THE COURSE OF EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS AND IS MAINLY DUE TO DISEASE-RELATED SEQUELAE

Background:Following the introduction of effective immunosuppressive treatments, ANCA-associated vasculitides (AAV) have become chronic diseases with a remitting-relapsing course. Therefore, preventing chronic damage accrual during follow-up is critical, as relapses, treatment-related side effects, and comorbidities may significantly affect the long-term outcomes of AAV patients. At present, no study specifically evaluated the burden of damage in patients with eosinophilic granulomatosis with polyangiitis (EGPA).Objectives:To describe short-term (6 months) and long-term (5 years) damage accrual in patients with newly diagnosed EGPA.Methods:Patients diagnosed with EGPA, according to ACR criteria and/or Chapel Hill definitions and regularly followed-up in our vasculitis center for ≥5 years were included. Damage accrual was assessed with the Vasculitis Damage Index (VDI). Short-term and long-term damage accrual was defined by VDI at 6 months and at 5 years, respectively, and categorized as related to vasculitis or its treatment.Results:VDI data at 6 months were available for 45 EGPA patients: 24 (53.3%) female, mean age at diagnosis 51.6±13.0 years. ANCA were positive in 17 patients (37.8%), with MPO being the only detected enzyme immunoassay (EIA)-specificity. At 6 months mean VDI was 2.8±1.3; 25/45 (55.6%) and 6/45 patients (13.3%) presented ≥3 and ≥5 items, respectively, whilst only 1 patient (2.2%) showed no items of damage. VDI data at 5 years were available for 32/45 EGPA patients (71.1%): 16 (50%) female, mean age at diagnosis 51.5±13.1 years. MPO-ANCA were positive in 13 patients (40.6%). At 5 years mean VDI was 3.5±1.3, with 26/32 (81.3%) and 7/32 patients (21.9%) presenting ≥3 and ≥5 items, respectively; notably, no patients presented a VDI=0 at 5 years.The most frequent disease-related VDI items at 6 months and at 5 years were asthma, chronic sinusitis, peripheral neuropathy, cardiomyopathy, pulmonary function tests abnormalities and nasal blockage (Figure 1). Osteoporotic fractures, diabetes and systemic hypertension were the most commonly reported treatment-related items at 6 months and at 5 years (Figure 1). Damage accrual progressively rose during the 5-year follow-up (P=0.023), mainly due to disease-related items rather than treatment-related items both at 6 months (disease related VDI 2.6±1.2, treatment-related VDI 0.3±0.6) and at 5 years (disease related VDI 2.9±1.2, treatment-related VDI 0.6±0,7). No significant difference in terms of damage accrual was observed between ANCA-positive and ANCA-negative patients (P >0.5).Conclusion:In our cohort of EGPA patients damage accrual occurs early, with more than half of the patients displaying ≥3 VDI items already at 6 months. Poor control of previous disease activity, particularly ENT and respiratory manifestations, contributes to progressive damage accrual more than treatment side effects.Figure 1.Disease-related and treatment-related VDI items at 6 months and at 5 years in patients with EGPA.Disclosure of Interests:None declare

POS0830 FACTORS INFLUENCING PATIENT-REPORTED OUTCOMES IN ANCA-ASSOCIATED VASCULITIS

Background:Patient-reported outcomes (PROs) are currently poorly integrated in the clinical evaluation of disease activity in patients with ANCA-associated vasculitis (AAV).Objectives:To assess the distribution of the Patient Global Assessment (PtGA) in patients with AAV in stable remission, and to identify correlates of PtGA; to assess the discordance between PtGA score and PhGA.Methods:Patients with a diagnosis of AAV [eosinophilic granulomatosis with polyangiitis, granulomatosis with polyangiitis, microscopic polyangiitis] in stable, complete remission (defined by a BVAS=0) and with a Physician Global Assessment (PhGA)=0 were included. A questionnaire including several aspects of disease captured by PROs was collected. PtGA on a 0-100 mm visual analogue scale (VAS) was assessed, with higher scores representing higher/worse levels of disease activity. Similarly, VAS for pain, chronic damage according to the patient's opinion, general health (GH), fatigue, and sleep quality were collected. The worst symptom in the patient's opinion affecting the overall assessment of disease activity was recorded. The Cragg Hurdle model was used to assess the predictors of PtGA.Results:65 patients were included, female 57%, mean age 61±12 years. Mean disease duration at enrollment was 8±6 years. Mean vasculitis damage index (VDI) was 4.4 ±2.3, with 45% of patients having a VDI ≥ 5. Despite having been classified as being in remission, PtGA was elevated in 37% of patients. We explored several correlates of PtGA. Higher degree of damage accrual (VDI) did not influence the patient's evaluation of current disease activity. Similarly, we did not identify a correlation between older age, educational level, number of organ-systems involved, number of comorbidities, the number of previous major or minor relapses, higher disease duration, nor the type of AAV diagnosis (figure 1, panel A). Only sex significantly correlated with PtGA scores: 19 (51%) of female patients reported an elevated PtGA compared to only 5 (18%) of male (p=0.009). PtGA resulted to be significantly correlated with other (mostly modifiable) PROs including VAS pain, perception of the level of chronic damage accrual, GH, and fatigue (figure 1, panel B). The agreement between patients' and physicians' assessments of disease activity was 63%. Patients reported pain, followed by chronic respiratory symptoms to be the worst-experienced ongoing manifestations affecting their evaluation of disease activity.Conclusion:A significant proportion of patients with AAV considered to be in remission by the physician still declares to have persistent aspects of uncontrolled disease. PtGA is significantly influenced by persistent pain and fatigue, which warrant better assessment in the future.Disclosure of Interests:None declare

Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells

Schwann cells are key players in neuro-regeneration: They sense "alarm" signals released by degenerating nerve terminals and differentiate toward a proregenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (H2O2) is a key signal of Schwann cells' activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of H2O2 rewire the expression of several RNAs at both transcriptional and translational levels. Among the genes positively regulated at both levels, we identified an enriched cluster involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family. We show that both Annexin A2 (Anxa2) transcript and protein accumulate at the tips of long pseudopods that Schwann cells extend upon H2O2 exposure. Interestingly, Schwann cells reply to this signal and to nerve injury by locally translating Anxa2 in pseudopods, and undergo an extensive cytoskeleton remodeling. Our results show that, similarly to neurons, Schwann cells take advantage of local protein synthesis to change shape and move toward damaged axonal terminals to facilitate axonal regeneration

the new edition of reumatismo

Ilettori più attenti si accorgeranno che in questo numero di Settembre 2008, Reumatismo presenta delle novità, alcune formali di piccolo significato, altre rilevanti, che riguardano soprattutto la composizione del Board. Crediamo che sia doveroso spiegare ai nostri lettori i motivi di questi cambiamenti. Reumatismo è sicuramente uno fra i più vecchi giornali scientifici di Reumatologia esistenti al mondo, essendo stato fondato nel 1949. Da allora ha rappresentato un punto di riferimento fondamentale per la Società Italiana di Reumatologia (SIR), come dimostra l'acquisizione precoce ed il successivo mantenimento della proprietà, e l'invio gratuito a tutti i soci..

Thrombotic thrombocytopenic purpura and autoimmunity: a tale of shadows and suspects

Background and Objective, The key pathogenic feature of TTP is the formation of platelet aggregates within the microcirculation; however, the etiology of such aggregates has been elusive for years. A large amount of evidence points to an abnormal interaction between damaged vascular endothelium and platelets, although the cause of the primary microvascular endothelial cell injury is seldom clear. The autoimmune hypothesis often recurs, and this is based on a number of observations: the claimed superiority of plasma-exchange over plasma infusion, the anecdotal report of the presence of immunocomplexes and autoantibodies in TTP patients, the efficacy of the administration of corticosteroids and other immunosuppressant agents, and the concomitant occurrence of TTP in association with autoimmune diseases, especially systemic lupus erythematosus (SLE). This review will focus on the complex relationships between TTP and humoral autoimmunity; in particular, similarities and differences between TTP, SLE and antiphospholipid (aPL) antibodies syndrome, as well as the putative role of several other antibodies directed towards endothelial cells and/or platelets, including the recently discovered anti-CD36 antibodies and antivWF-cleaving metalloprotease, will be discussed. Design and Methods. The authors have been Involved in the study and treatment of TTP and autoimmune diseases for years; furthermore, the PubMed data base of the National Library of Congress has been extensively searched using the Internet. Conclusions. Although over the years evidence has increased in favor of the autoimmune hypothesis for TTP etiopathogenesis, TTP should not yet be considered an autoimmune disease. Autoantibodies should be regarded as only one of the many different insults which can trigger microvascular thrombosis even though the autoimmune theory of the pathogenesis of TTP is gaining more and more strength. As far as concerns the relationship between TTP, SLE and aPL antibodies-related disorders, these diseases should be distinguished on the basis of both different clinical presentations and accurate antibody screening, although this approach should definitely not delay the prompt start of treatment